Derivatives of 5,5-diphenylhydantoin exhibiting enhanced solubility and the therapeutic use thereof

ABSTRACT

Novel derivatives of 5,5-diphenylhydantoin, having the formula: ##STR1## wherein R is as defined in the specification and claims hereinafter, are disclosed. These compounds exhibit enhanced solubility over diphenylhydantoin per se and find therapeutic usefulness as anticonvulsants, antiepileptics and antiarrhythmics.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to novel and therapeutically usefulderivatives of phenytoin. More particularly, the present inventionconcerns the discovery of a group of novel derivatives of phenytoinwhich offer enhanced solubility over phenytoin per se.

These compounds are extremely useful as anticonvulsants, antiepilepticsand antiarrhythmics and can be administered to warm-blooded animals(e.g., humans) per se or in pharmaceutical composition form when admixedwith a suitable nontoxic pharmaceutically acceptable carrier.

2. Description of the Prior Art

A pharmaceutical and medical need exists for new and useful compoundsindicated from the management of epilepsy and other types of convulsivestates, and cardiac arrythmics. The need exists because compounds suchas 5,5-diphenylhydantoin, generally referred to as diphenylhydantoin orphenytoin, which is most commonly and widely used for the treatment ofthese conditions possess extremely low solubility and hence, lowbioavailability per se as well as from pharmaceutical dosage forms. Forexample, 5,5-diphenylhydantoin which has a therapeutic index between 1and 2, a pKa of 8.3, and a solubility of less than 2 mg. in 100 ml at37° C. often produces unpredictable and erractic release patterns, bothin vitro and in vivo. Also, when 5,5-diphenylhydantoin is orallyadministered in the form of its sodium salt, it frequently causesgastric irritation due to the alkalinity of the administered dosageform. For intravenous administration, sodium 5,5-diphenylhydantoin isgenerally used in a formulation comprising 40% propylene glycol and 10%alcohol in water, adjusted with sodium hydroxide to a high alkaline pH.Intravenous administration of this formulation frequently leads toprecipitation of 5,5-diphenylhydantoin as well as erractic blood levels.Intramuscular use of sodium 5,5-diphenylhydantoin has been shown toprecipitate 5,5-diphenylhydantoin at the injection site leading todelayed and erractic 5,5-diphenylhydantoin release. Other hydantoinshave similar problems to those seen with 5,5-diphenylhydantoin. Thiscommon and wide use of the hydantoins with their accompanyingdisadvantages, and specifically, their low solubilities, creates animmediate and pressing need for new and useful pharmaceutical compoundsthat possess therapeutic properties useful for treating epilepsy andother convulsive states, and cardiac arrythmics, while remainingessentially free from the unwanted effects associated with the prior artcompounds.

U.S. Pat. No. 3,595,862 claims the potential usefulness ofN,N'-bis(acyloxymethyl)5,5-diphenylhydantoin compounds as effectiveanticonvulsants. The compounds of this patent include those in which theacyloxy groups are acetoxy, acryloxy, methacryloxyloxy, propionoxy andbenzoyloxy. The compounds are inferior in solubility to the compoundsclaimed in this application and in fact have solubility characteristicssimilar to 5,5-diphenylhydantoin itself.

SUMMARY OF THE INVENTION

Accordingly, it is an immediate object of this invention to providenovel pharmaceutical compounds that are useful as antiepileptics,anticonvulsants and antiarrythmics.

Another object of this invention is to provide novel and usefulderivatives of diphenylhydantoin which are characterized as beingsubstantially more soluble than the parent specie per se.

Still, another object of this invention is to provide novel and useulderivatives of diphenylhydantoin which, in addition to exhibitingenhanced solubility, are essentially free from the unwanted effectsassociated with the physical and chemical properties of prior artderivatives.

Finally, another object of the present invention is to provide new anduseful derivatives of diphenylhydantoin as characterized above whichfurther exhibit enhanced stability such that they can be tolerated inconventional pharmaceutical dosage formulations.

All the foregoing objects are achieved by administering to awarm-blooded animal in need of anticonvulsants and/or antiepileptictherapy, a compound having the formula: ##STR2## wherein R represents Hor a member selected from the group consisting of ##STR3## wherein R₁represents a member selected from the group consisting of H, C₁ -C₇straight or branched alkyl, CCl₃, CBr₃, CI₃, ##STR4## wherein R₃represents a member selected from the group consisting of --OH, halogen(Cl, Br, I), --OCH₃, --COOCH₃, --NO₂ or --OCOCH₃ ; wherein X is --O--,--S--, or ##STR5## and wherein R₂ represents a member selected from thegroup consisting of ##STR6## wherein R₄ is a member selected from thegroup consisting of ##STR7## wherein R₃ is defined as above, ##STR8##the residue of any naturally occurring protein amino acid, the residueof any N- substituted amino acid, wherein said substituent is any aminoacid protective group cleavable via hydrogenolysis or hydrolysis (e.g,formyl, benzyloxy, carbonyl, t-butyloxycarbonyl) or the residue of anN,N-C₁ -C₅ -dialkyl or C₄ -C₇ cycloalkylamino acid, or wherein R₄ is amember selected from the group consisting of ##STR9## wherein nrepresents an integer of from 1-5 and R₅ and R₆ which may be the same ordifferent represent C₁ -C₅ alkyl or together form a heterocyclic ringwith the N atom to which they are attached (e.g., pyrolidine,piperidine, morpholine, piperazine, imidazoline, thiazolidine), orwherein R₄ is a member selected from the group consisting of imidazolyl,--O--C₁ C₈ alkyl, --O-benzyl, --O-phenyl, and ##STR10## wherein n, R₅and R₆ are defined as above; with the proviso that R is both occurrencescannot represent H simultaneously; or the pharmaceutically acceptableacid addition or basic salts, C₁ -C₄ alkylhalide quaternary salts orN-oxide thereof.

While all the compounds encompassed within the above generic formulasuffice for the applicants' purposes, nevertheless, certain selectedcompounds are preferred as noted below. A "most" preferred group ofcompounds is claimed hereinafter.

1. 3-Ethoxycarbonyloxymethyl-diphenylhydantoin.

2. 3-Benzyloxycarbonyloxymethyl-diphenylhydantoin.

3. 3-(2',2',2'-Trichloroethyloxycarbonyloxymethyl)-diphenylhydantoin.

4. 3-(N,N-Dimethylglycyloxymethyl)-diphenylhydantoin.

5. 3-(1-Piperidylacetyloxymethyl)-diphenylhydantoin.

6. 3-Benzoyloxymethyl-diphenylhydantoin.

7. 3-p-Toluyloxymethyl-diphenylhydantoin.

8. 3-Picolinoyloxymethyl-diphenylhydantoin.

9. 3-Nicotinoyloxymethyl-diphenylhydantoin.

10. 3-N-Formylglycyloxymethyl-diphenylhydantoin.

11. 3-Glycyloxymethyl-diphenylhydantoin.

12. 3-N-Benzyloxycarbonylglycyloxymethyl-diphenylhydantoin.

13. 3-Methylsuccinyloxymethyl-diphenylhydantoin.

14. 3-(N,N-Dimethylsuccinamyloxymethyl)-diphenylhydantoin.

15. 3-(N,N-Diethylsuccinamyloxymethyl)-diphenylhydantoin.

16. 3-(N,N,N-Trimethylglycyloxymethyl)-diphenylhydantoin.

17. 3-(N,N,N-Trimethylglycyloxymethyl)-diphenylhydantoin.

18. 3-[α-(N,N-Dimethylglycyloxy)ethyl]-diphenylhydantoin.

19. 3-[α-(1-Piperidylacetyloxy)ethyl]-diphenylhydantoin.

20. 3-(α-Benzoyloxyethyl)-diphenylhydantoin.

21. 3-(α-Picolinoyloxyethyl)-diphenylhydantoin.

22. 3-[α-(N-Formylglycyloxy)ethyl]-diphenylhydantoin.

23. 3-[α-(N-Benzyloxycarbonylglycyloxy)ethyl]-diphenylhydantoin.

24. 3-(α-Methylsuccinyloxyethyl)-diphenylhydantoin.

25. 3-[α-(N,N-Dimethylsuccinamyloxy)ethyl]-diphenylhydantoin.

26. 3-[α-(N,N,N-Trimethylglycyloxy)ethyl]-diphenylhydantoin chloride.

27. 3-(α-Ethoxycarbonyloxybenzyl)-diphenylhydantoin.

28. 3-[α-(N,N-Dimethylglycyloxy)benzyl]-diphenylhydantoin.

29. 3-[α-(1-Piperidylacetyloxy)benzyl]-diphenylhydantoin.

30. 3-(α-Picolinoyloxybenzyl)-diphenylhydantoin.

31. 3-[α-N-Formylglycyloxy)benzyl]-diphenylhydantoin.

32. 3-[α-N-Benzyloxycrbonylglycyloxy)benzyl]-diphenylhydantoin.

33. 3-(α-Methylsuccinyloxybenzyl)-diphenylhydantoin.

34. 3-[α-(N,N-Dimethylsuccinamyloxy)benzyl]-diphenylhydantoin.

35. 3-[α-(N,N,N-Trimethylglycyloxy)benzyl]-diphenylhydantoin chloride.

36. 3-(N,N-Dimethylglycylthiomethyl)-diphenylhydantoin.

37. 3-(1-Piperidylacetylthiomethyl)-diphenylhydantoin.

38. 3-p-Toluylthiomethyl-diphenylhydantoin.

39. 3-Picolinoylthiomethyl-diphenylhydantoin.

40. 3-Nicotinoylthiomethyl-diphenylhydantoin.

41. 3-N-Formylglycylthiomethyl-diphenylhydantoin.

42. 3-Glycylthiomethyl-diphenylhydantoin.

43. 3-(N,N-Diethylsuccinamylthiomethyl)-diphenylhydantoin.

44. 3-(N,N,N-Trimethylglycylthiomethyl)-diphenylhydantoin chloride.

45. 3-(N,N,N-Triethylglycylthiomethyl)-diphenylhydantoin chloride.

46. 3-Phosphoryloxymethyl-diphenylhydantoin.

47. 3-Succinyloxymethyl-diphenylhydantoin.

48. 3-Glutaryloxymethyl-diphenylhydantoin.

A "most" preferred group of compounds are claimed hereinafter.

The phrase "non-toxic . . . addition salts" as used herein generallyincludes the non-toxic acid or basic addition salts of the compoundswithin the above-described generic formula, formed with non-toxicinorganic and organic acids or bases. For example, the former saltsinclude those derived from inorganic acids such as hydrochloric,hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; andthe salts prepared from organic acids such a acetic, propionic,succinic, glycollic, stearic, lactic, malic, tartaric, citric, ascorbic,pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic,salicylic, sulfanilic, fumaric, toluenesulfonic methanesulfonate, andthe like. The latter salts include those derived from alkali or alkalineearth metal bases or conventional organic bases, e.g., triethylamine,pyridine, piperidine, morpholine, N-methylmorpholine, etc.

The term "naturally occurring protein amino acid" includes withoutlimitation:

    ______________________________________                                        Glycine               Arginine                                                Alanine               Lysine                                                  Valine                Hydroxylsine                                            Leucine               Phenylalanine                                           Isoleucine            Tyrosine                                                Cysteine              Asparagine                                              Cystine               Glutamine                                               Methionine            Proline                                                 Serine                Hydroxyproline                                          Threonine             Histidine                                               Aspartic acid         Tryptophan                                              Glutamic acid         Pyroglutamic acid                                       ______________________________________                                    

Similarly, the import of the phrase "amino acid protective group`cleavable` via hydrogenolysis or hydrolysis" can be further gained froma review of U.S. Pat. No. 3,803,120--Felix and U.S. Pat. No.3,957,803--Bodor, et al.

All the compounds within generic formula (I) are prepared by way ofreaction schemes (I) or (II) set out below, wherein R, R₁, R₂ and R₄ aredefined as above; and wherein X represents an oxygen, sulfur or nitrogenatom, M represents an alkali or alkaline earth metal (Na, K, Ca, Mg) orthallium, and wherein Y represents a halogen atom, e.g., F, Cl, Br or I.Unless otherwise stated, all reactants are employed in stoichiometricamounts and all reactions are run at standard temperature and pressure.##STR11##

In reaction scheme (I), the use of a solvent is optional. When desired,however, water is sufficient. When using a coupling agent in the finalstep of converting the compound of formula (IV) to the final compound offormula (I), any suitable conventional organic coupling agent can beemployed. Illustrative of such agents are DCCI and EEDQ. Additionalcoupling agents can be ascertained from the text entitled "CHEMISTRY OFAMINO ACIDS" (1964), McGraw-Hill. Finally, the reaction for scheme (I)is run at standard temperature and pressure, over a period of from oneto 24 hours.

With respect to reaction scheme (II), the reaction is run in a solventcomprising any suitable organic material such as dimethylformamide,ether, halogenated hydrocarbon, etc. The reaction is normally run over aperiod of from one to 24 hours at standard pressure and at a temperatureranging from room temperature to the boiling point of the solventsselected.

When using either reaction scheme, the final compound of formula (I) canbe obtained via standard crystallization procedures, and if necessary,recrystallization can be carried out in the presence of any suitableorganic solvent.

In reference to reaction scheme (I), the intermediate compound offormula (IV) is also deemed novel by the applicant, and accordingly, isclaimed hereinafter.

The non-toxic pharmaceutically acceptable acid addition salts oracceptable basic salts C₁ -C₄ quaternary alkylhalides or N-oxides of thepresent invention can be synthesized from the compounds embraced byformula (I) by conventional chemical methods. Normally, the salts areprepared by reacting the free base or acid with stoichiometric amountsor with an excess thereof of the desired salt forming inorganic ororganic acid or base in a suitable solvent or various combination ofsolvents. As an example, the free base or acid can be dissolved in anaqueous solution of the appropriate acid or base and the salt recoveredby standard techniques, for example, by evaporation of the solution.Alternatively, the free base or acid can be dissolved in an organicsolvent such as a lower alkanoyl, an ether, an alkyl ester, or mixturesthereof, for example, methanol, ethanol, ether, ethylacetate, anethylacetate-ether solution, and the like, whereafter it is treated withthe appropriate acid or base to form the corresponding salt. The salt isrecovered by standard recovery techniques, for example, by filtration ofthe desired salt on spontaneous separation from the solution, or it canbe precipitated by the addition of a solvent in which the salt isinsoluble and recovered therefrom.

The quaternary alkylhalides and N-oxides are prepared in similar fashionby reacting the compound of formula of formula (I) with thecorresponding alkylhalide or N-oxide.

Without further elaboration, it is believed that one of ordinary skillin the art can, using the preceding description, utilize the presentinvention to its fullest extent. Accordingly, the following preferredspecific embodiments are, therefore, to be construed as merelyillustrative and not limitative of the remainder of the specificationand claims in any way whatsoever.

PREPARATION OF THE 3-(HYDROXYMETHYL)DIPHENYLHYDANTOIN PRECURSOR

20 g of 5,5-diphenylhydantoin (0.08 moles) and 80 ml (32 g) of formalinare introduced into a suitable reaction vessel containing 720 ml ofwater and one g of potassium carbonate. The reaction is stirred at roomtemperature for 24 hours, after which the subject compound, mp186.5°-188.5° C., yield 22.58 g (91.86%) is obtained by filtration.

EXAMPLE I--PREPARATION OF SOME SELECTED COMPOUNDS OF FORMULA (I)PREPARATION OF 3-(N,N-DIMETHYLGLYCYLOXYMETHYL)DIPHENYLHYDANTOIN

Into a suitable reaction vessel containing 5 ml of pyridine, there isadded one g (0.035 mols) of 3-hydroxymethyl-diphenylhydantoin, 0.36 g(0.0035 mols) of N,N-dimethylglycine and 0.79 g (0.0035 mols) ofdicyclohexylcarbodiimide (DCCI). The reaction mixture is stirred at roomtemperature for a period of approximately 24 hours, after which thefinal product, mp 128°-130°, yield 0.86 g (66.7%) is obtained.

PREPARATION OF 3-(N,N-DIMETHYLGLYCYLOXYMETHYL)DIPHENYLHYDANTOINMETHANESULFONATE

Into a suitable reaction vessel containing a sufficient amount ofdichloromethane (CH₂ Cl₂), there was introduced 0.310 g (0.0032 mols) ofmethylsulfonic acid (CH₃ SO₃ H) and 1.18 g (0.0032 mols) ofN,N-dimethylglycyloxymethyl-diphenylhydantoin. The reaction mixture wasstirred at room temperature overnight after which the subject compound,mp 173°-175° C., yield 2.25 g (92.6%) was obtained.

PREPARATION OF 3-(N,N-DIMETHYLGLYCYLOXYMETHYL)DIPHENYLHYDANTOINSALICYLATE

By following the immediately preceding reaction scheme but substitutinga stoichiometric amount of salicylic acid for methylsulfonic acid, thesubject compound was obtained in quantitative yield.

PREPARATION OF 3-(GLUTARYLOXYMETHYL)DIPHENYLHYDANTOIN

To a suitable reaction vessel containing 25 ml of pyridine, there wasadded 10 g (0.0354 mols) of 3-hydroxymethyldiphenylhydantoin and 4.85 g(0.0425 mols) of glutaric anhydride. The reaction mixture was stirred atroom temperature for 5 days, thus obtaining the subject compound, mp137.5°-146° C., yield 7.90 g (56.0%).

PREPARATION OF 3-(SUCCINYLOXYMETHYL)DIPHENYLHYDANTOIN

To a suitable reaction vessel containing 25 ml of pyridine, there wasadded 10 g (0.0354 mols) of 3-hydroxymethyldiphenylhydantoin and 4.25 g(0.0425 mols) of succinyl anhydride. The reaction mixture was stirred atroom temperature for 5 days after which the subject compound, mp141.5°-146° C. yield 8.36 g (62.0%) was obtained.

In similar fashion, the remaining compounds of the present invention canbe prepared with similar success by merely following the precedingexamples and substituting the generally and/or specifically describedreactants and/or operating conditions of this invention for those of thepreceding examples.

The improved solubility of the novel compounds of the instant inventionis demonstrated via 3-(N,N-dimethylglycyloxymethyl)diphenylhydantoinmethanesulfonate, a selective compund from within formula (I). Thecompound was added in increments to water until solubility wasdetermined. The solubility for the subject compound was in excess of 100mg/ml which is quite dramatic when compared to the solubility of theparent specie, diphenylhydantoin per se, i.e., less than 0.02 mg/ml(approximate 5,000 fold increase in aqueous solubility overdiphenylhydantoin).

When repeating the above-described solubility experiment, but this time,employing the remaining compounds of formula (I), substantially improvedsolubility characteristics over diphenylhydantoin are observed.

The novel and useful diphenylhydantoin compounds of this invention canbe used by the pharmaceutical and the veterinary arts for theirantiepileptic, anticonvulsant and antiarrhythmic effects in a variety ofpharmaceutical or veterinary preparations. In these preparations, thenew compounds are administrable in the form of tablets, pills, powdermixtures, capsules, injectables, solutions, suppositories, emulsions,dispersions, food premix, and in other suitable form. The pharmaceuticalor veterinary preparation which contains the compound is convenientlyadmixed with a nontoxic pharmaceutical organic carrier or a nontoxicpharmaceutical inorganic carrier, usually about 0.01 mg up to 2500 mg,or higher per dosage unit. Typical of pharmaceutically acceptablecarriers are, for example, lactose, potato and maize starches, magnesiumstearate, talc, vegetable oils, polyalkylene glycols, ethyl cellulose,poly(vinylpyrrolidone), calcium carbonate, ethyl oleate, isopropylmyristate, benzyl benzoate, sodium carbonate, gelatin, potassiumcarbonate, silicic acid, and other conventionally employed acceptablecarriers. The pharmaceutical preparation may also contain nontoxicauxiliary substances such as emulsifying, preserving, wetting agents,and the like, as for example, sorbitan monolaurate, triethanolamineoleate, polyoxyethylene monostearate, glyceryl tripalmitate, dioctylsodium sulfosuccinate, and the like.

Exemplary of a typical method for preparing a tablet containing theactive agents is to first mix the agent with a nontoxic binder such asgelatin, acacia mucilage, ethyl cellulose, or the like. The mixing issuitably carried out in a standard V-blender and usually under anhydrousconditions. Next, the just prepared mixture can be slugged throughconventional tablet machines and the slugs fabricated into tablets. Thefreshly prepared tablets can be coated, or they can be left uncoated.Representative of suitable coatings are the nontoxic coatings includingshellac, methylcellulose, carnauba wax, styrene-maleic acid copolymers,and the like. For oral administration, compressed tablets containing0.01 milligram, 5 milligrams, 25 milligrams, 50 milligrams, etc., up to2500 milligrams are manufactured in the light of the above disclosureand by art known fabrication techniques well known to the art and setforth in Remington's Pharmaceutical Science, Chapter 39, Mack PublishingCo., 1965. The pharmaceutical manufacture of a formulation is shown inExample II.

EXAMPLE II

    ______________________________________                                        Ingredients:            Per tablet, mg.                                       ______________________________________                                        3-(N,N-dimethylglycyloxymethyl)-                                              diphenylhydantoin methanesulfonate                                                                    50.0                                                  Cornstarch              15.0                                                  Cornstarch paste        4.5                                                   Calcium carbonate       15.0                                                  Lactose                 67.0                                                  Calcium stearate        2.0                                                   Dicalcium phosphate     50.0                                                  ______________________________________                                    

To formulate the tablet uniformly blend the active compound, cornstarch,lactose, dicalcium phosphate and calcium carbonate under dry conditionsin a conventional V-blender until all the ingredients are uniformlymixed together. Next, the cornstarch paste is prepared as a 10% pasteand it is blended with the just prepared mixture until a uniform mixtureis obtained. The mixture is then passed through a standard light meshscreen, dried in an anhydrous atmosphere and then blended with calciumstearate, and compressed into tablets, and coated if desired. Othertablets containing 10, 50, 100, 150 mgs, etc., are prepared in a likefashion.

EXAMPLE III

    ______________________________________                                        Ingredients:            Per tablet, mg.                                       ______________________________________                                        3-(N,N-dimethylglycyloxymethyl)-                                              diphenylhydantoin methanesulfonate                                                                    50.0                                                  Cornstarch              15.0                                                  Cornstarch paste        4.5                                                   Calcium carbonate       15.0                                                  Lactose                 67.0                                                  Calcium stearate        2.0                                                   Dicalcium phosphate     50.0                                                  ______________________________________                                    

The manufacture of capsules containing 10 milligrams to 2500 milligramsfor oral use consists essentially of mixing the active compound with anontoxic carrier and enclosing the mixture in a polymeric sheath,usually gelatin or the like. The capsules can be in the art known softform of a capsule made by enclosing the compound in intimate dispersionwithin an edible, compatible carrier, or the capsule can be a hardcapsule consisting essentially of the novel compound mixed with anontoxic solid such as talc, calcium stearate, calcium carbonate, or thelike. Exemplary of a typical use for employing a capsule containing 100mg of 3-(N,N-dimethylglycyloxymethyl)diphenylhydantoin methanesulfonatefor use as therapeutically indicated ad libitum for antiepilepticeffects. Capsules containing 25 mg, 75 mg, 125 mg, and the like, of thenovel compounds, singularly or mixtures of two or more of the novelcompounds are prepared, for example, as follows: EXAMPLE IV

    ______________________________________                                        Ingredients:            Per capsule, mg.                                      ______________________________________                                        Active compound of formula (I)                                                                        50.0                                                  Calcium carbonate       100.0                                                 Lactose, U.S.P.         200.0                                                 Starch                  130.0                                                 Magnesium stearate      4.5                                                   ______________________________________                                    

The above ingredients are blended together in a standard blender andthen discharged into commercially available capsules. When higherconcentrations of the active agent is used, a corresponding reduction ismade in the amount of lactose.

The dose administered, whether a single dose, multiple dose, or a dailydose, will of course, vary with the particular compound of the inventionemployed because of the varying potency of the compound, the chosenroute of administration, the size of the recipient and the nature of thearrythmia or epileptic seizure and other states characterized byinvoluntary movements such as Parkinson's syndrome. The dosageadministered is not subject to definite bounds, but it will usually bean effective amount, or the equivalent on a molar basis of thepharmacologically active free form produced from a dosage formulationupon the metabolic release of the active drug to achieve its desiredpharmacological and physiological effects. The dosage administered forthe management of cardiac arrythmias, grand mal, petit mal, psychomotorequivalent seizures and other forms of convulsive seizures is formammals, including primates and humans a general oral dose of 200 to 800mg daily, with the oral dose of normally 100 mg up to 4 times a day; theusual intravenous dose of 100 to 350 mg, followed by if indicated 100 to150 mg at a later period, and the usual intramuscular dose of 100 to 300mg every 6 to 8 hours, with 3 to 4 injections per day. For householdanimals, such as dogs, the administrable dose is about 30 to 200 mgabout every 6 to 8 hours.

For administering to valuable household animals, such as dogs, or foradministering to laboratory animals such as mice, for scientificstudies, the compound is prepared in the form of an injectable, or inthe form of a food premix, such as mixing with dry meal, mash and thelike, and then the prepared premix is added to the regular feed, therebyadministering the compound to the domestic or laboratory animal.

The novel therapeutic compounds of the invention can also be formulatedinto compositions comprising other compounds useful in the symptomatictherapy of cardiac arrhthmias, epilepsy and other states characterizedby involuntary movements such as chorea and Parkinson's syndrome. Forexample, 3-(N,N-dimethylglycyloxymethyl)diphenylhydantoinmethanesulfonate, can be mixed with 5,5-diphenyl-2,4-imidazolidinedionefor oral administration at the rate of 200 mg to 600 mg daily, forexample, as administered in capsule form. Typical capsules comprise 15mg or 50 mg of 3-(N,N-dimethylglycyloxymethyl)diphenylhydantoinmethanesulfonate and 15 mg or 50 mg of5,5-diphenyl-2,4-imidazolidinedione for oral administration up to 4times a day.

The novel and useful hydantoates of the invention are adaptable foradministration for their physiological anti-epileptic and anticonvulsanteffects from drug delivery systems, such as skin delivery systems,gastrointestinal drug delivery devices, and the like, wherein thedelivery device is manufactured from naturally occurring and syntheticpolymeric materials. Representative of materials acceptable for thefabrication of drug delivery systems containing the compounds forcontrolled drug administration include materials such as polyvinylchloride, polyisoprene, polybutadiene, polyethylene, ethylene-vinylacetate copolymers, polydimethylsiloxane, hydrophillic hydrogels ofesters of acrylic and methacrylic acid, polyvinyl acetates,propylenevinyl acetate copolymers, and the like.

It is also quite obvious that due to the extremely exceptionalsolubility characteristics of the claimed compounds overdiphenylhydantoin per se and derivatives of the prior art, superiorparenteral formulation and administration is achieved. Similarly,improved oral bioavailability is achieved owing to the increasedsolubility of the subject compounds.

From the foregoing description, it is obvious that one of ordinary skillin the art can easily ascertain the essential characteristics of thisinvention, and without departing from the spirit and scope thereof, canmake various changes and/or modifications to the invention for adaptingit to various usages and conditions. As such, these changes andmodifications are properly, equitably and intended to be, within thefull range of equivalence of the following claims.

What we claim is:
 1. A 5,5-diphenylhydantoin compound having theformula: ##STR12## wherein R represents H or a member selected from thegroup consisting of ##STR13## wherein R₁ represents a member selectedfrom the group consisting of H and C₁ -C₇ straight or branched alkyl;wherein X is --O-- or --S--; and wherein R₂ represents ##STR14## whereinR₄ is an acyl residue of any naturally occurring protein amino acid;with the proviso that R in both occurrences cannot represent Hsimultaneously; or the pharmaceutically acceptable acid addition orbasic salts, C₁ -C₄ alkylhalide quaternary salts or N-oxide thereof. 2.The compound of claim1:3-(N,N-Dimethylglycyloxymethyl)diphenylhydantoin.
 3. The compound ofclaim 1:3-(N,N-Dimethylglycyloxymethyl)diphenylhydantoinmethanesulfonate.
 4. The compound of claim1:3-(N,N-Dimethylglycyloxymethyl)diphenylhydantoin salicylate.
 5. Apharmaceutical composition comprising an effective anticonvulsant,antiepileptic or antiarrythmic amount of a 5,5-diphenylhydantoincompound having the formula: ##STR15## wherein R represents H or amember selected from the group consisting of ##STR16## wherein R₁represents a member selected from the group consisting of H and C₁ -C₇straight or branched alkyl; wherein X is --O-- or --S--; and wherein R₂represents ##STR17## wherein R₄ is an acyl residue of any naturallyoccurring protein amino acid; with the proviso that R is bothoccurrences cannot represent H simultaneously; or the pharmaceuticallyacceptable acid addition or basic salts; C₁ -C₄ alkylhalide quaternarysalts or N-oxide thereof in combination with a pharmaceuticallyacceptable inert carrier.
 6. The combination of claim 5, wherein saidcompound is:3-(N,N-Dimethylglycyloxymethyl)diphenylhydantoin.
 7. Thecomposition of claim 5, wherein said compoundis:3-(N,N-Dimethylglycyloxymethyl)diphenylhydantoin methanesulfonate. 8.The composition of claim 5, wherein sid compoundis:3-(N,N-Dimethylglycyloxymethyl)diphenylhydantoin salicylate.
 9. Amethod for alleviating cardia arrythmias or convulsions in awarm-blooded animal which comprises administering thereto, an effectiveantiarrythmic or anticonvulsant amount of a 5,5-diphenylhydantoincompound having the formula: ##STR18## wherein R represents H or amember selected from the group consisting of ##STR19## wherein R₁represents a member selected from the group consisting of H or C₁ -C₇straight or branched alkyl; wherein X is --O-- or --S--; and wherein R₂represents ##STR20## wherein R₄ is an acyl residue of any naturallyoccurring protein amino acid; with the proviso that R in bothoccurrences cannot represent H simultaneously, or the pharmaceuticallyacceptable acid addition or basic salts, C₁ -C₄ alkylhalide quaternarysalts or N-oxide thereof.
 10. The method of claim 12, wherein saidcompound is administered in combination with a pharmaceuticallyacceptable inert carrier.
 11. The method of claim 9, wherein saidcompound is:3-(N,N-Dimethylglycycloxymethyl)diphenylhydantoin.
 12. Themethod of claim 9, wherein said compoundis:3-(N,N-Dimethylglycyloxymethyl)diphenylhydantoin methanesulfonate.13. The method of claim 9, wherein said compoundis:3-(N,N-Dimethylglycyloxymethyl)diphenylhydantoin salicylate.